A genetic research program is proposed to generate by gene targeting mouse mutants lacking the functions of the breast cancer susceptibility genes Brca1 and Brca2 and examine whether they could serve as model simulating human predisposition to mammary tumors. To bypass the embryonic lethality associated with the global ablation of the Brca1 and Brca2 functions, these genes will be inactivated only in the mammary glands by conditional targeted mutagenesis using the cre/loxP system. Using these models in a breeding program, mammary tumor progression will be investigated in a background null for growth signaling effected by insulin-like growth factors (IGFs). Recent evidence demonstrating a central involvement of the IGF system in cell transformation and tumorigenesis has provided a strong indication for the proposed genetic analyses. To initiate our investigation, we have advanced a working hypothesis postulating that tumor development will be prevented or reduced in severity in a genetic background null for a major signalling pathway regulating growth. Thus, the development of mammary tumors in mice lacking the BRCA1 or BRCA2 tumor suppressors will be examine in the absence of the type 1 IGF receptor (IGF1R). Similarly, progression of a variety of tumors will be studied by combining p53 and Igf1r null mutations, because relationships between the pathway of the p53 tumor suppressor and the IGFs have been noted. The proposed studies, which have the advantage that questions will be addressed in vivo in the context of the entire experimental organism, should allow the establishment of causal relationships between defined mutations and their phenotypic consequences for the multi-step process of carcinogenesis, and are likely to provide information of practical significance for the eventual identification of candidate targets for rational therapeutic regimes.